Currently there is no cure for osteoporosis and the development of therapeutic treatments remains limited. Present day therapies involve anti-resorptive agents such as bisphosphonates, estrogen analogs, raloxifene and calcitonin which primarily target bone resorbing osteoclasts resulting in reduced bone turnover. However anti-resorptive therapies are not associated with significant increases in bone mass and therefore only partially reduce fracture risk and prevent the normal bone remodeling required to maintain bone health. Thus, a significant need exists for the development of additional bone anabolic agents to prevent or treat this debilitating disease. This project explores the actions of endoxifen, a tamoxifen metabolite, on the skeleton and its mechanism of action in bone cells. Preliminary data suggests that endoxifen increases quality and structure of bone in conditions of reduced estrogen as is seen in osteoporosis and may be more favorable than other new generation breast cancer therapies which exhibit significant deleterious skeletal effects. Therefore, the central hypothesis is that endoxifen, a novel SERM, elicits bone anabolic effects by increasing, rather than decreasing, bone formation thereby functioning differently than that of other SERMs. The goals of this proposal are to characterize in vivo effects on the skeleton using a mouse model system and to identify the molecular mechanisms by which endoxifen, as compared to tamoxifen and raloxifene, exerts its effects on cultured osteoblasts, and osteoclasts. PUBLIC HEALTH RELEVANCE: Osteoporosis and Breast Cancer are major burdens on society. Endoxifen is a newly identified as the primary active metabolite of Tamoxifen, one of the major therapeutic selective estrogen receptor modulators used in Breast Cancer therapy today. My preliminary studies have shown that Endoxifen is also a potent anabolic agent on the skeleton. Similar to Estrogen action on bone remodeling, my studies have indicated that Endoxifen maintains/enhances overall bone formation via enhanced remodeling. These studies have the potential to identify Endoxifen as a novel, highly beneficial, therapeutic agent for osteopenia, osteoporosis and other bone related disorders, as well as breast cancer therapy